{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:02:31Z","timestamp":1787029351875,"version":"build-2736575974"},"reference-count":52,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000266","name":"Engineering and Physical Sciences Research Council","doi-asserted-by":"publisher","award":["EP\/S019227\/1"],"award-info":[{"award-number":["EP\/S019227\/1"]}],"id":[{"id":"10.13039\/501100000266","id-type":"DOI","asserted-by":"publisher"}]},{"name":"EPSRC Centre for Doctoral Training in Formulation Engineering","award":["EP\/L015153\/1"],"award-info":[{"award-number":["EP\/L015153\/1"]}]}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["Pharmaceutics"],"abstract":"<jats:p>The performance of solid oral dosage forms targeting the colon is typically evaluated using standardised pharmacopeial dissolution apparatuses. However, these fail to replicate colonic hydrodynamics. This study develops a digital twin of the Dynamic Colon Model; a physiologically representative in vitro model of the human proximal colon. Magnetic resonance imaging of the Dynamic Colon Model verified that the digital twin robustly replicated flow patterns under different physiological conditions (media viscosity, volume, and peristaltic wave speed). During local contractile activity, antegrade flows of 0.06\u20130.78 cm s\u22121 and backflows of \u22122.16\u2013\u22120.21 cm s\u22121 were measured. Mean wall shear rates were strongly time and viscosity dependent although peaks were measured between 3.05\u201310.12 s\u22121 and 5.11\u201320.34 s\u22121 in the Dynamic Colon Model and its digital twin respectively, comparable to previous estimates of the USPII with paddle speeds of 25 and 50 rpm. It is recommended that viscosity and shear rates are considered when designing future dissolution test methodologies for colon-targeted formulations. In the USPII, paddle speeds &gt;50 rpm may not recreate physiologically relevant shear rates. These findings demonstrate how the combination of biorelevant in vitro and in silico models can provide new insights for dissolution testing beyond established pharmacopeial methods.<\/jats:p>","DOI":"10.3390\/pharmaceutics14010184","type":"journal-article","created":{"date-parts":[[2022,1,14]],"date-time":"2022-01-14T03:14:03Z","timestamp":1642130043000},"page":"184","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Simulating the Hydrodynamic Conditions of the Human Ascending Colon: A Digital Twin of the Dynamic Colon Model"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4857-7768","authenticated-orcid":false,"given":"Michael","family":"Sch\u00fctt","sequence":"first","affiliation":[{"name":"School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4888-8892","authenticated-orcid":false,"given":"Connor","family":"O\u2019Farrell","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7524-2800","authenticated-orcid":false,"given":"Konstantinos","family":"Stamatopoulos","sequence":"additional","affiliation":[{"name":"School of Chemical Engineering, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK"},{"name":"Biopharmaceutics, Pharmaceutical Development, PDS, MST, RD Platform Technology & Science, GSK, David Jack Centre, Park Road, Ware, Hertfordshire SG12 0DP, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5483-1027","authenticated-orcid":false,"given":"Caroline L.","family":"Hoad","sequence":"additional","affiliation":[{"name":"Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UK, UK"},{"name":"Sir Peter Mansfield Imaging Centre, School of Physics and Astronomy, University of Nottingham, Nottingham NG7 2RD, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9092-4300","authenticated-orcid":false,"given":"Luca","family":"Marciani","sequence":"additional","affiliation":[{"name":"Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UK, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9170-8255","authenticated-orcid":false,"given":"Sarah","family":"Sulaiman","sequence":"additional","affiliation":[{"name":"Nottingham Digestive Diseases Centre and National Institute for Health Research (NIHR) Nottingham Biomedical Research Centre, Nottingham University Hospitals NHS Trust and University of Nottingham, Nottingham NG7 2UK, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark J. 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(2019). MRI of the Colon in the Pharmaceutical Field: The Future before us. Pharmaceutics, 11.","DOI":"10.3390\/pharmaceutics11040146"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"893","DOI":"10.3109\/03639049709148695","article-title":"Colonic drug delivery","volume":"23","author":"Watts","year":"1997","journal-title":"Drug Dev. Ind. Pharm."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.compbiomed.2017.01.003","article-title":"Using discrete multi-physics for detailed exploration of hydrodynamics in an in vitro colon system","volume":"81","author":"Alexiadis","year":"2017","journal-title":"Comput. Biol. Med."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Sch\u00fctt, M., Stamatopoulos, K., Batchelor, H.K., Simmons, M.J.H., and Alexiadis, A. (2021). Modelling and Simulation of the Drug Release from a Solid Dosage Form in the Human Ascending Colon: The Influence of Different Motility Patterns and Fluid Viscosities. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13060859"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"103819","DOI":"10.1016\/j.compbiomed.2020.103819","article-title":"Modelling and simulation of the hydrodynamics and mixing profiles in the human proximal colon using Discrete Multiphysics","volume":"121","author":"Stamatopoulos","year":"2020","journal-title":"Comput. Biol. Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.ejpb.2016.08.004","article-title":"Dissolution profile of theophylline modified release tablets, using a biorelevant Dynamic Colon Model (DCM)","volume":"108","author":"Stamatopoulos","year":"2016","journal-title":"Eur. J. Pharm. Biopharm."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Stamatopoulos, K., Karandikar, S., Goldstein, M., O\u2019Farrell, C., Marciani, L., Sulaiman, S., Hoad, C.L., Simmons, M.J.H., and Batchelor, H.K. (2020). Dynamic Colon Model (DCM): A Cine-MRI Informed Biorelevant In Vitro Model of the Human Proximal Large Intestine Characterized by Positron Imaging Techniques. Pharmaceutics, 12.","DOI":"10.3390\/pharmaceutics12070659"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.compbiomed.2012.01.002","article-title":"Investigating the relationships between peristaltic contraction and fluid transport in the human colon using Smoothed Particle Hydrodynamics","volume":"42","author":"Sinnott","year":"2012","journal-title":"Comput. Biol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"143","DOI":"10.1016\/j.apm.2017.01.034","article-title":"Peristaltic transport of a particulate suspension in the small intestine","volume":"44","author":"Sinnott","year":"2017","journal-title":"Appl. Math. Model."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1016\/j.ijpharm.2015.09.002","article-title":"Understanding the impact of media viscosity on dissolution of a highly water soluble drug within a USP 2 mini vessel dissolution apparatus using an optical planar induced fluorescence (PLIF) method","volume":"495","author":"Stamatopoulos","year":"2015","journal-title":"Int. J. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ijpharm.2018.01.002","article-title":"Computational hydrodynamic comparison of a mini vessel and a USP 2 dissolution testing system to predict the dynamic operating conditions for similarity of dissolution performance","volume":"539","author":"Wang","year":"2018","journal-title":"Int. J. Pharm."},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"O\u2019Farrell, C., Hoad, C.L., Stamatopoulos, K., Marciani, L., Sulaiman, S., Simmons, M.J.H., and Batchelor, H.K. (2021). Luminal Fluid Motion Inside an In Vitro Dissolution Model of the Human Ascending Colon Assessed Using Magnetic Resonance Imaging. Pharmaceutics, 13.","DOI":"10.3390\/pharmaceutics13101545"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1443","DOI":"10.1111\/nmo.12408","article-title":"Quantification of in vivo colonic motor patterns in healthy humans before and after a meal revealed by high-resolution fiber-optic manometry","volume":"26","author":"Dinning","year":"2014","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"113924","DOI":"10.1016\/j.addr.2021.113924","article-title":"In vitro models to evaluate ingestible devices: Present status and current trends","volume":"178","author":"Stamatopoulos","year":"2021","journal-title":"Adv. Drug Deliver. Rev."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.ijpharm.2010.04.044","article-title":"The transit of dosage forms through the colon","volume":"395","author":"Wilson","year":"2010","journal-title":"Int. J. Pharm."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"20201024","DOI":"10.1098\/rsif.2020.1024","article-title":"The virtual physiological human gets nerves! How to account for the action of the nervous system in multiphysics simulations of human organs","volume":"18","author":"Alexiadis","year":"2021","journal-title":"J. R. Soc. Interface"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Alexiadis, A. (2015). The Discrete Multi-Hybrid System for the Simulation of Solid-Liquid Flows. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0124678"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1016\/j.piutam.2015.03.010","article-title":"A new framework for modelling the dynamics and the breakage of capsules, vesicles and cells in fluid flow","volume":"16","author":"Alexiadis","year":"2015","journal-title":"Proc. Iutam."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1016\/j.ejps.2019.04.013","article-title":"Impact of regional differences along the gastrointestinal tract of healthy adults on oral drug absorption: An UNGAP review","volume":"134","author":"Vertzoni","year":"2019","journal-title":"Eur. J. Pharm. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1007\/s003480000110","article-title":"Velocity measurements of flow through a step stenosis using Magnetic Resonance Imaging","volume":"29","author":"Moser","year":"2000","journal-title":"Exp. Fluids"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ariane, M., Allouche, M.H., Bussone, M., Giacosa, F., Bernard, F., Barigou, M., and Alexiadis, A. (2017). Discrete multi-physics: A mesh-free model of blood flow in flexible biological valve including solid aggregate formation. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0174795"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1016\/j.compbiomed.2018.01.010","article-title":"Discrete multi-physics simulations of diffusive and convective mass transfer in boundary layers containing motile cilia in lungs","volume":"95","author":"Ariane","year":"2018","journal-title":"Comput. Biol. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"96","DOI":"10.1016\/j.compbiomed.2017.07.020","article-title":"Modelling and simulation of flow and agglomeration in deep veins valves using discrete multi physics","volume":"89","author":"Ariane","year":"2017","journal-title":"Comput. Biol. Med."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Baksamawi, H.A., Ariane, M., Brill, A., Vigolo, D., and Alexiadis, A. (2021). Modelling Particle Agglomeration on through Elastic Valves under Flow. ChemEngineering, 5.","DOI":"10.3390\/chemengineering5030040"},{"key":"ref_25","doi-asserted-by":"crossref","unstructured":"Mohammed, A.M., Ariane, M., and Alexiadis, A. (2020). Using Discrete Multiphysics Modelling to Assess the Effect of Calcification on Hemodynamic and Mechanical Deformation of Aortic Valve. ChemEngineering, 4.","DOI":"10.20944\/preprints202004.0107.v1"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"051903","DOI":"10.1063\/1.5091999","article-title":"Deformation and rupture of compound cells under shear: A discrete multiphysics study","volume":"31","author":"Rahmat","year":"2019","journal-title":"Phys. Fluids"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"123314","DOI":"10.1063\/5.0029213","article-title":"Modeling the agglomeration of settling particles in a dewatering process","volume":"32","author":"Rahmat","year":"2020","journal-title":"Phys. Fluids"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.commatsci.2018.04.037","article-title":"Natural convection and solidification of phase-change materials in circular pipes: A SPH approach","volume":"150","author":"Alexiadis","year":"2018","journal-title":"Comp. Mater. Sci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"57","DOI":"10.1016\/j.compfluid.2018.01.037","article-title":"Using Discrete Multi-Physics for studying the dynamics of emboli in flexible venous valves","volume":"166","author":"Ariane","year":"2018","journal-title":"Comput. Fluids"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1108\/HFF-05-2019-0437","article-title":"Numerical simulation of dissolution of solid particles in fluid flow using the SPH method","volume":"30","author":"Rahmat","year":"2020","journal-title":"Int. J. Numer. Methods Heat Fluid Flow"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.artmed.2019.06.005","article-title":"Deep multiphysics: Coupling discrete multiphysics with machine learning to attain self-learning in-silico models replicating human physiology","volume":"98","author":"Alexiadis","year":"2019","journal-title":"Artif. Intell. Med."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Alexiadis, A. (2019). Deep Multiphysics and Particle-Neuron Duality: A Computational Framework Coupling (Discrete) Multiphysics and Deep Learning. Appl. Sci., 9.","DOI":"10.3390\/app9245369"},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Sanfilipo, D., Bahman, G., Alexiadis, A., and Hernandez Garcia, A. (2021). Combined Peridynamics and Discrete Multiphysics to Study the Effects of Air Voids and Freeze-Thaw on the Mechanical Properties of Asphalt. Materials, 14.","DOI":"10.3390\/ma14071579"},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Liu, G.R., and Liu, M.B. (2003). Smoothed Particle Hydrodynamics: A Meshfree Particle Method, World Scientific.","DOI":"10.1142\/9789812564405"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1339","DOI":"10.1007\/s00371-014-1015-5","article-title":"Elastic moduli of simple mass spring models","volume":"31","author":"Kot","year":"2015","journal-title":"Vis. Comput."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1081","DOI":"10.1109\/TVCG.2007.1055","article-title":"Identification of spring parameters for deformable object simulation","volume":"13","author":"Lloyd","year":"2007","journal-title":"IEEE Trans. Vis. Comput. Graph."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1007\/s11242-012-9955-6","article-title":"Lattice Spring Models","volume":"93","author":"Pazdniakou","year":"2012","journal-title":"Transp. Porous Media"},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Mohammed, A.M., Ariane, M., and Alexiadis, A. (2021). Fluid-Structure Interaction in Coronary Stents: A Discrete Multiphysics Approach. ChemEngineering, 5.","DOI":"10.20944\/preprints202106.0733.v1"},{"key":"ref_39","doi-asserted-by":"crossref","unstructured":"Sahputra, I.H., Alexiadis, A., and Adams, M.J. (2020). A Coarse Grained Model for Viscoelastic Solids in Discrete Multiphysics Simulations. ChemEngineering, 4.","DOI":"10.3390\/chemengineering4020030"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1086\/112164","article-title":"A numerical approach to the testing of the fission hypothesis","volume":"82","author":"Lucy","year":"1977","journal-title":"Astron. J."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"374","DOI":"10.1016\/0021-9991(83)90036-0","article-title":"Shock Simulation by the Particle Method SPH","volume":"52","author":"Monaghan","year":"1983","journal-title":"J. Comput. Phys."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1703","DOI":"10.1088\/0034-4885\/68\/8\/R01","article-title":"Smoothed Particle Hydrodynamics","volume":"68","author":"Monaghan","year":"2005","journal-title":"Rep. Prog. Phys."},{"key":"ref_43","unstructured":"Birmingham, U. (2021, September 01). University of Birmingham\u2019s BlueBEAR HPC Service. Available online: http:\/\/www.birmingham.ac.uk\/bear."},{"key":"ref_44","unstructured":"Ganzenm\u00fcller, G.C., Steinhauser, M.O., and Van Liedekerke, P. (2019, October 17). The Implementation of Smoothed Particle Hydrodynamics in LAMMPS, Available online: Lammps.sandia.gov\/doc\/PDF\/SPH_LAMMPS_userguide.pdf."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1006\/jcph.1995.1039","article-title":"Fast Parallel Algorithms for Short-Range Molecular-Dynamics","volume":"117","author":"Plimpton","year":"1995","journal-title":"J. Comput. Phys."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"015012","DOI":"10.1088\/0965-0393\/18\/1\/015012","article-title":"Visualization and analysis of atomistic simulation data with OVITO-the Open Visualization Tool","volume":"18","author":"Stukowski","year":"2010","journal-title":"Model. Simul. Mater. Sci. Eng."},{"key":"ref_47","unstructured":"MATLAB (2020). MATLAB 9.9.0.1495850 (R2020b), The MathWorks Inc."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"210","DOI":"10.1002\/jmri.21395","article-title":"MRI phase contrast velocity and flow errors in turbulent stenotic jets","volume":"28","author":"Cowan","year":"2008","journal-title":"J. Magn. Reson. Imaging"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"148","DOI":"10.1111\/j.1365-2982.2004.00587.x","article-title":"Magnetic pill tracking: A novel non-invasive tool for investigation of human digestive motility","volume":"17","author":"Stathopoulos","year":"2005","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1911","DOI":"10.1016\/j.xphs.2018.03.019","article-title":"Using Computational Fluid Dynamics to Compare Shear Rate and Turbulence in the TIM-Automated Gastric Compartment With USP Apparatus II","volume":"107","author":"Hopgood","year":"2018","journal-title":"J. Pharm. Sci."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"345-e167","DOI":"10.1111\/j.1365-2982.2011.01870.x","article-title":"Solid-state vs. water-perfused catheters to measure colonic high-amplitude propagating contractions","volume":"24","author":"Liem","year":"2012","journal-title":"Neurogastroenterol. Motil."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"G660","DOI":"10.1152\/ajpgi.1988.255.5.G660","article-title":"Manometric investigation of high-amplitude propagated contractile activity of the human colon","volume":"255","author":"Bassotti","year":"1988","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."}],"updated-by":[{"DOI":"10.3390\/pharmaceutics14071402","type":"correction","label":"Correction","source":"publisher","updated":{"date-parts":[[2022,1,13]],"date-time":"2022-01-13T00:00:00Z","timestamp":1642032000000}}],"container-title":["Pharmaceutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/184\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,3]],"date-time":"2025-08-03T22:19:55Z","timestamp":1754259595000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4923\/14\/1\/184"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,13]]},"references-count":52,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["pharmaceutics14010184"],"URL":"https:\/\/doi.org\/10.3390\/pharmaceutics14010184","relation":{},"ISSN":["1999-4923"],"issn-type":[{"value":"1999-4923","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,13]]}}}